tbuckley/cabot-search huggingface dataset:
Relationship between the humoral link of immunity, cytokine regulation with short-chain fatty acids in patients with inflammatory bowel diseases
Authors: Yu.M. Stepanov, M.V. Stoikevych, I.A. Klenina, O.M. Tatarchuk
Journal: GASTROENTEROLOGY (2022)

Background. The pathogenesis of chronic inflammatory bowel disease (IBD) is still not fully clarified. Modern research is aimed at studying the state of humoral immunity, production and intestinal absorption of short-chain fatty acids (SCFA). The purpose was to assess the state of the humoral part of immunity, cytokine regulation and the content of short-chain fatty acids in the feces of patients with IBD. Materials and methods. The study, which was carried out at the Department of Intestinal Diseases of the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine, involved 34 patients with IBD: groupI— those with ulcerative colitis (UC) (n=25), group II— individuals with Crohn’s disease (n=9). Determination of fecal SCFA, level of CD22+ lymphocytes, immunoglobulins A, M, G, interleukin-10 and TNF-α was determined. Results. There was a decrease in the humoral level of immunity, increase in the content of propionic (C3) acid (p&lt;0.001) and a decrease in acetic (C2) (p&lt;0.001) and butyric (C4) (p&lt;0.001) acids in the coprofiltrate of patients with IBD. The level of TNF-α was significantly higher in patients with mild UC (13.3 times, p&lt;0.05), in patients with moderate UC (17.4 times, p&lt;0.05) and in patients with Severe UC (19.4 times, p &lt;0.05) compared with its level in the control group; it was found that in the group of patients with severe UC there was a significant decrease in the content of butyric acid (C4) in 2.8 times relative to the control group (p&lt;0,01). Conclusions. In our study, a relationship was established between the level of humoral immunity, cytokine regulation and the content of FFA in feces, which may indicate the participation of intestinal metabolites in the activation of human immunity.
Abstract 5624: PD-L1 mediates IFNγ-regulation of glucose but not of tryptophan metabolism in clear cell renal cell carcinoma
Authors: Mamatha Garige, Susmita Ghosh, ALexis Norris, Guangyuan Li, Carole Sourbier
Journal: Cancer Research (2022)

Abstract The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed cell death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following PD-L1 transient silencing. Aerobic glycolysis as well as signaling pathways related to inflammation were not induced by IFNγ when PD-L1 was silenced, however tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals. Citation Format: Mamatha Garige, Susmita Ghosh, ALexis Norris, Guangyuan Li, Carole Sourbier. PD-L1 mediates IFNγ-regulation of glucose but not of tryptophan metabolism in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5624.
Abstract 549: The IgG4 hinge with CD28 transmembrane domain mediates CAR dimerization and improves the activity of glypican 1-targeted CAR T cells in pancreatic cancer
Authors: Nan Li, Dan Li, Jiajia Pan, Raul Cachau, Mitchell Ho
Journal: Cancer Research (2022)

Abstract Low antigen density has been suggested as a major cause of insufficient antitumor activity of chimeric antigen receptor (CAR) T cells. The impact of the hinge and the transmembrane (TM) domain on modulating CAR T cell reactivity is important to investigate. Here, we isolated a camel nanobody D4 recognizing glypican 1 (GPC1), a cell surface proteoglycan that is expressed in pancreatic cancer. We constructed a series of D4 4-1BBζ CARs differing only by their hinge (CD8 or IgG4) and TM (CD8 or CD28). D4 CARs containing a mutated IgG4 hinge and the CD28 TM, but not CD8 hinge with either TM, formed dimers in human T cells and resulted in improved stability of the CAR extracellular domain in a 3D structure model. The CAR dimerization increased phosphorylation of T cell signaling molecules, activated non-canonical NF-κB signaling after antigen stimulation. Consequently, the D4-IgG4 hinge-CD28TM CAR T cells triggered the most cytokine secretion and showed the best reactivity against low GPC1-expressing pancreatic tumor cells among all the D4 CARs in vitro and in vivo. Conversely, a CAR with mutations of the two cysteine residues in the IgG4 hinge disrupted CAR dimerization, damaged the formation of TM, and resulted in the loss of improved reactivity. Furthermore, adding extra spacers of CH3 or CH2CH3 between IgG4 hinge and CD28TM CAR attenuated the CAR activity. By optimizing the hinge and TM, our data indicated that 4-1BBζ CAR T cell activity can be optimized against low antigen density tumors. Citation Format: Nan Li, Dan Li, Jiajia Pan, Raul Cachau, Mitchell Ho. The IgG4 hinge with CD28 transmembrane domain mediates CAR dimerization and improves the activity of glypican 1-targeted CAR T cells in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 549.
Abstract 1526: Circulatory insulin-like growth factor 1 predicts metastasis in triple-negative breast cancer
Authors: Salima Akter, Mithila Faruque, Hajara Akhter, Mousumi Bhowmik, Mohammad Nazmul Hasan, Lipika Sultana, Imran Khan, Mamun Mia, Md. Mustafizur Rahman, Habib Sadat Chaudhury, Islam S. Rafiqul, Kamrun Nahar, Tae Gyu Choi, Sung Soo Kim
Journal: Cancer Research (2022)

Abstract Background and aims: Aberrant insulin-like growth factor (IGFs) signaling is directly implicated in oncogenesis and metastasis in various solid tumors including breast cancer. Targeting the IGF axis may provide an insight into the mechanism of cancer stemness and therapy resistance. The present study aims to explore the association of the circulatory levels of these proteins in aggressive triple-negative breast cancer (TNBC) in Bangladesh. Methods: A total of 165 BC patients were recruited in the present study where 42 were TNBC subjects (selected based on their complete hormonal profile). Data were collected from retrospective information. Anthropometric and biochemical parameters were measured by standard methods. Serum IGF1, IGFBP1, and insulin were estimated by ELISA. Results: TNBC subjects showed significantly higher levels of circulatory IGF1 (185 vs 145, p=0.004), while patients who had distant metastasis showed increased levels of IGF1, IGFBP1, and alkaline phosphatase (ALP) [178 vs 153, p=0.001; 6.44 vs 3.05, and 140 vs 88, p&amp;lt;0.05; metastatic vs non-metastatic BC respectively]. In addition, serum IGF1 was positively associated with serum insulin levels and IGFBP1 was associated with ALP, SGPT, CA15.3, and duration of OCP (p&amp;lt;0.05). In multivariate regression, IGF1 was found to be a significant predictor of breast cancer survival after adjusting confounding variables. Conclusion: High serum levels of IGF1 may contribute to metastasis in basal breast cancer in a Bangladeshi population. These results need to be confirmed in larger TNBC survivor cohorts. Citation Format: Salima Akter, Mithila Faruque, Hajara Akhter, Mousumi Bhowmik, Mohammad Nazmul Hasan, Lipika Sultana, Imran Khan, Mamun Mia, Md. Mustafizur Rahman, Habib Sadat Chaudhury, Islam S. Rafiqul, Kamrun Nahar, Tae Gyu Choi, Sung Soo Kim. Circulatory insulin-like growth factor 1 predicts metastasis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1526.
Abstract 992: MUC13 enhances colorectal cancer metastasis through molecular interaction with YAP1 transcription factor
Authors: Kyle Doxtater, Manish K. Tripathi, Radhika Sekhri, Sudhir Kotnala, Bilal Hafeez, Sheema Khan, Nadeem Zafar, Murali Yallapu, Meena Jaggi, Subhash Chauhan
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. About 90% of all cancer-related deaths are due to the development of metastatic sites in the body. 40-50% of colorectal cancer patients develop metastasis at some point during their fight with the disease. Understanding the mechanism of metastasis in colorectal cancer is vital. Metastasis is a multistep process; anchorage-independent survival after intravasation of cells from the primary tumor site is a crucial step. In our lab, we have previously demonstrated that MUC13 plays an essential role in the CRC progression by modulating anti-apoptotic pathways and survival proteins expression. Under anchorage-independent growth conditions, we have identified that MUC13, in correspondence with YAP1, is the key upregulated protein and is responsible for increased survival. Isogenic CRC cell lines SW480 (non-metastatic) and SW620 (metastatic) on low adherence growth conditions are applied in these studies. In addition, lentiviral transduced stable overexpression and knockdown cell lines were generated for MUC13 and YAP1 mechanistic studies. The overexpression of MUC13 in non-metastatic SW480 cells (low MUC13 expressing) increased anchorage-independent survival and enhanced tumorigenesis compared to SW480+Vector cells, contrary results were found upon MUC13 knockdown in SW620 cells (high MUC13 expressing). In vitro results were recapitulated in the in vivo mouse model system and human CRC tissues. In Proximity Ligation Assays (PLA), we found an increased nuclear localization of the survival complex YAP1/β-catenin in MUC13 overexpressing cells. In contrast, MUC13 knockdown resulted to the lower aboudance of survival complex in the nucleus. Immunoprecipitation validates the protein-protein interaction between MUC13 and YAP1. YAP1 knockdown in MUC13 overexpressing cells showed a decrease in survival, indicating the necessary functional complex formation between MUC13 and YAP1. MUC13 and YAP1 expression in human CRC tissue were highest at Stage II. However, YAP1 expression increased when MUC13 was observed in the nucleus. This supports the notion that MUC13 is critical in enhancing CRC metastasis through molecular interaction with YAP1. For the first time, this study demonstrates complex formation between MUC13 and YAP1 and defines their role in CRC progression and metastasis. Citation Format: Kyle Doxtater, Manish K. Tripathi, Radhika Sekhri, Sudhir Kotnala, Bilal Hafeez, Sheema Khan, Nadeem Zafar, Murali Yallapu, Meena Jaggi, Subhash Chauhan. MUC13 enhances colorectal cancer metastasis through molecular interaction with YAP1 transcription factor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 992.
Abstract 2260: Non-alcoholic fatty liver disease polygenic risk score and risk of hepatocellular carcinoma in an East Asian population
Authors: Claire E. Thomas, Brenda Diergaarde, Allison L. Kuipers, Jennifer J. Adibi, Hung N. Luu, Xuling Chang, Rajkumar Dorajoo, Chew-Kiat Heng, Chiea-Chuen Khor, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan
Journal: Cancer Research (2022)

Abstract Purpose: It is difficult to identify people with non-alcoholic fatty liver disease (NAFLD) who are at high risk for the development of hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population level data of this risk in non-European populations are lacking. Methods: Utilizing resources from the Singapore Chinese Health Study (SCHS), we examined the relationship between the previously published hepatic fat PRS (HFC-PRS) and HCC risk. We also constructed and evaluated a NAFLD-related PRS (NAFLD-PRS); the final version included SNPs in similar gene regions as the HFC-PRS but weighted by effect estimates for NAFLD among those with East Asian ancestry. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. Results: The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, P &amp;lt; 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared to their respective lowest quartile. Conclusion: The HFC-PRS and the NAFLD-PRS may both be useful in stratifying Asian populations according to their risk of HCC. In addition, the association between the NAFLD-PRS, derived from East Asians, and HCC risk suggests a potential causal role for NAFLD in the development of HCC in this population. Citation Format: Claire E. Thomas, Brenda Diergaarde, Allison L. Kuipers, Jennifer J. Adibi, Hung N. Luu, Xuling Chang, Rajkumar Dorajoo, Chew-Kiat Heng, Chiea-Chuen Khor, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Non-alcoholic fatty liver disease polygenic risk score and risk of hepatocellular carcinoma in an East Asian population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2260.
Abstract 3077: Leveraging a 3D organoid library to identify novel therapeutic targets during ESCC initiation and progression
Authors: Samuel Flashner, Masataka Shimonosono, Satoshi Takada, Norihiro Matsuura, Yasuto Tomita, Xiao Chen, Alison Taylor, Andres Klein-Szanto, Fatameh Momen-Heravi, J. Alan Diehl, Chao Lu, Hiroshi Nakagawa
Journal: Cancer Research (2022)

Abstract Esophageal squamous cell carcinoma (ESCC) is a devastating and common disease worldwide. Despite recent advances annotating the genetic and epigenetic changes underlying the initiation and development of ESCC and its precursor lesion, esophageal squamous dysplasia, more work is needed to translate these findings into novel therapeutic strategies. This gap is due in part to the lack of tractable models of ESCC initiation and development that can then be manipulated ex vivo for preclinical testing. Currently, the large-scale studies characterizing the aforementioned molecular changes have used primary tissue for their analyses and have subsequently been unable to test the specific hypotheses that arise from their data using the original tissue that they profiled. To address this gap, we have generated a large (n = 54) three-dimensional organoid library from the esophagi of mice treated with the carcinogen 4-Nitroquinoline N-oxide (4-NQO) representing each stage of esophageal squamous cell initiation and progression from early intraepithelial dysplasia through lung metastasis. We have determined that these organoids faithfully recapitulate the molecular biology, histology, and oncogenic phenotype of their tissue of origin. Through integrative analysis of both RNA sequencing and whole exome sequencing data, we have identified several novel therapeutic targets that contribute to ESCC initiation and development including the DNA damage response and NOTCH1 signaling. Together, our work capitalizes on the intersection of large-scale multiomics and sophisticated 3D organoid models to identify novel therapeutic targets for the treatment of a devastating disease. Citation Format: Samuel Flashner, Masataka Shimonosono, Satoshi Takada, Norihiro Matsuura, Yasuto Tomita, Xiao Chen, Alison Taylor, Andres Klein-Szanto, Fatameh Momen-Heravi, J. Alan Diehl, Chao Lu, Hiroshi Nakagawa. Leveraging a 3D organoid library to identify novel therapeutic targets during ESCC initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3077.
Error in Role of the Funder/Sponsor
Journal: JAMA Network Open (2022)

Gwen T. Lapham, PhD, MPH, MSW; Theresa E. Matson, MPH; David S. Carrell, PhD; Jennifer F. Bobb, PhD; Casey Luce, MSPH; Malia M. Oliver, BA; Udi E. Ghitza, PhD; Clarissa Hsu, PhD, MPH; Kendall C. Browne, PhD; Ingrid A. Binswanger, MD, MPH, MS; Cynthia I. Campbell, PhD; Andrew J. Saxon, MD; Ryan Vandrey, PhD; Gillian L. Schauer, PhD, MPH; Rosalie Liccardo Pacula, PhD; Michael A. Horberg, MD, MAS; Steffani R. Bailey, PhD; Erin A. McClure, PhD; Katharine A. Bradley, MD, MPH
Abstract 5903: Polygenic risk scores for prediction of breast cancer in Korean women
Authors: Yon Ho Jee, Weang-Kee Ho, Sohee Park, Douglas Easton, Soo-Hwang Teo, Keum Ji Jung, Peter Kraft
Journal: Cancer Research (2022)

Abstract Background: Polygenic risk scores (PRS) developed in large European GWAS have been shown to perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk prediction models combining lifestyle and PRS in Asian women is limited. We evaluate the calibration of four PRS developed using Asian or European training samples; two PRS were restricted to genome-wide significant SNPs (GRS-11ASN, GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN, PRS-209EUR). Methods: For each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models among 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions (reference inputs) among U.S. women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. Results: All Asian and European PRS improved risk prediction for breast cancer in Korean women (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age less than 50). We found that the U.S.-based absolute risk models overestimated the risks for women age ≥50 years (PRS-42ASN: E/O=1.93, 95% CI=1.69, 2.19, PRS-209EUR: E/O = 1.92, 95% CI=1.69, 2.19). Our absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. Conclusions: Incorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women. Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity. Larger Asian training samples should improve PRS discrimination among Korean women. Further studies are needed to evaluate the value of incorporating additional information on factors into a model in ancestrally diverse populations. Citation Format: Yon Ho Jee, Weang-Kee Ho, Sohee Park, Douglas Easton, Soo-Hwang Teo, Keum Ji Jung, Peter Kraft. Polygenic risk scores for prediction of breast cancer in Korean women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5903.
Abstract 436: Rapid flow cytometric whole blood assay for assessment of SARS-CoV-2-reactive T cell immunity
Authors: Lorenz Fülle, Philipp David Gert, Verena Traska, Sofia Chatzopoulou, Christian Dose, Anne Richter, Marc Schuster
Journal: Cancer Research (2022)

Abstract As of November 2021, the viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has infected more than 250 million individuals worldwide and killed over 5 million people. In addition to known risk groups, also cancer patients are at increased risk for severe disease progression. Therefore, understanding the nature of the accompanying immune response is essential, especially the role of T cells for successful virus defense but also during immunopathology leading to severe disease outcomes. Furthermore, as neutralizing antibodies are reported to decay within months post infection or vaccination or are even absent due to cancer treatment, SARS-CoV-2-specific T cell persistence is discussed as an indicator of long-term protective immunity. Especially, in immunocompromised cancer patients, levels of SARS-CoV-2-specifc antibodies may not be efficiently detected. Therefore, we developed a rapid and easy flow cytometric assay for the analysis of SARS-CoV-2-reactive CD4+ and CD8+ T cells directly from whole blood. Citation Format: Lorenz Fülle, Philipp David Gert, Verena Traska, Sofia Chatzopoulou, Christian Dose, Anne Richter, Marc Schuster. Rapid flow cytometric whole blood assay for assessment of SARS-CoV-2-reactive T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 436.
Abstract 2310: Histone methyltransferase-independent function of EZH2 in the cell cycle regulation
Authors: Tania Marlyn Colon, Byeong Hyeok Choi, Wei Dai
Journal: Cancer Research (2022)

Abstract Enhancer of zeste homologue 2 (EZH2) is an evolutionarily conserved histone methyltransferase that mediates the methylation of lysine 27 of histone H3 (H3K27me3). EZH2 is frequently mutated or overexpressed in many types of cancer. Extensive research in the past has revealed that EZH2 forms part of the polycomb repressive complex 2 (PRC2), an essential multi-protein complex required for gene silencing and chromatin compaction. EZH2 also displays additional cellular functions that include transcriptional activation of certain gene expression and methylation of non-histone substrates, the latter modulating protein stability or actin polymerization. Moreover, EZH2 is known to play a role in regulating cell cycle progression. However, it remains unclear whether EZH2 has an enzyme-independent function in the cell cycle. Here we show that EZH2 knockdown by small interfering RNAs (siRNAs) results in an increased expression of cyclin-dependent kinase inhibitors including p21, p27, and p57, which is associated with G1/S arrest. We have also observed that HeLa cells treated with Tazemestostat, a specific EZH2 inhibitor, display a significant reduction in H3K27me3. However, Tazemestostat treatment neither increases expression of p21, p27, and p57 nor induces cell cycle arrest. Taken together, our findings suggest a novel mechanism by which EZH2 regulates cell cycle progression through its enzyme-independent function. Citation Format: Tania Marlyn Colon, Byeong Hyeok Choi, Wei Dai. Histone methyltransferase-independent function of EZH2 in the cell cycle regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2310.